1. Field of the Invention
The occurrence of xe2x80x9cdrug resistancexe2x80x9d is the main reason for failure in cancer chemotherapy. Tumors which initially react sensitively to cytostatic agents very frequently recover after a certain treatment time and then are resistant to the effects of various types of antineoplastic drugs. Although the problem of xe2x80x9cdrug resistancexe2x80x9d has been known since 1948 (the year when cancer therapy with cytostatic agents began), until now no way has been known of preventing the formation of resistance.
A characteristic of all highly resistant tumors and cell strains investigated to date is the amplification (multiplication) of a small group of genes. As a result of this DNA or gene amplification, an increased expression of these genes is exhibited, which can lead to resistance to the drug. As a result of this DNA amplification an increased expression of various genes occurs. Protective proteins which serve to shuttle toxins out of the cell can thus be formed in increased quantities (e.g., P-glycoprotein). This effect is also known as xe2x80x9cmulti-drug resistancexe2x80x9d (MDR).
In addition to MDR, the degree of amplification of certain genes, especially certain oncogenes, correlates with the degree of malignancy. Thus, the chances of survival with an amplification of ERVV2, RASKI, INT3, HST1, MYC and KSRAM in stomach cancer are very poor. See Hirohasi, S., and Sugimura, T., xe2x80x9cGenetic Alterations in Human Gastric Cancer, Cancer cells (Cold Spring Harbor), 3:49-52 (1991). The chances of survival with an amplification of and ERBB2 and MYC in ovarian carcinoma are also very poor. See Sasano, H., Garrett, C. T., Wilkinson, D. C., Silverberg, S., Comerford, J., and Hyde, J., xe2x80x9cProtooncogene Amplification and Tumor Ploidy in Human Ovarian Neoplasmxe2x80x9d, Hum. Pathol., 21:382-391 (1990).
In breast cancer, the amplification of MYC correlates with the progress of the disease. See Borg, A., Baldetorp, B., Fernxc3x6, M. Olsson, H., and Sigurdsson, H., xe2x80x9cC-myc Amplification is an Independent Prognostic Factor in Postmenopausal Breast Cancerxe2x80x9d, Int. J. Cancer, 51:687-691 (1992). Likewise, in breast cancer, the coamplification of INT2 and HST1 correlates with the progress of the disease. See Borg, A., Sigurdsson, H., Clark, G. M., et al., xe2x80x9cAssociation of INT2/HST1 Coamplification in Primary Breast Cancer with Hormone-Dependent Phenotype and Poor Prognosisxe2x80x9d, Br.J.Cancer, 63:136142 (1991).
The amplification of ERBB2 and EGFR is linked to a poor prognosis. See Descotes, F., Pavy, J. -J., and Adessi, G. L., xe2x80x9cHuman Breast Cancer: Correlation Study Between HER-2/neu Amplification and Prognostic Factors in an Unselected Populationxe2x80x9d, Anticancer Res., 13:119-124 (1993) and Klijn, J. G. M., Berns, P. M. J. J., Schmitz, P. I. M., and Foekens, J. A., xe2x80x9cThe Clinical Significance of Epidermal Growth Factor Receptor (EGF-R) in Human Breast Cancer: A Review on 5232 Patientsxe2x80x9d, Endocr.Rev., 13:3-17 (1992).
In esophageal cancer, the coamplification of HST1 and INT2 correlates with the degree of metastasis. See Tsuda, T., Tahara, E., Kajiyama, G., Sakamoto, H., Terada, M., and Sugimura, T., xe2x80x9cHigh Incidence of Coamplification of HST-1 and INT-2 Genes in Human Esophageal Carcinomasxe2x80x9d, Cancer Res. 49:5505-5508, 1989).
In summary it can be ascertained that by means of chronic treatment with carcinogenic cytostatic agents, the induced gene amplification leads not only to resistance to this treatment, but also to the over-expression of certain oncogenes which control the degree of malignancy.
2. Discussion of Background
A series of substances have been described which counteract the acquired drug resistance. Included are those described in the work of Kennedy on the anti-carcinogenic effects of protease inhibitors. See Kennedy, A. R., xe2x80x9cPrevention of Carcinogenesis by Protease Inhibitorsxe2x80x9d, Cancer Res., 54:1999-2005 (1994). These substances can suppress carcinogen-induced gene amplification to almost normal levels. Kennedy observed that radiation-induced gene amplification is suppressed in the same way corresponding with its capacity to suppress radiation-induced transformation, so that a relationship between these two processes can be assumed. In addition, protease-inhibitors act as antagonists of (co-recombinogenic) tumor inducers during the initiation of transformation in vitro. Protease-inhibitors are also described as effective anti-promoters in in vivo experiments. See Troll, W., Klassen, A., and Janoff, A., xe2x80x9cTumorigenesis in Mouse Skin: Inhibition by Synthetic Inhibitors of Proteasesxe2x80x9d, Science (Washington D.C.) 169:1211-1213 (1970).
It is known that verapamil acts against MDR. See Moscow, I. A., and Cowan, K. H., xe2x80x9cMultidrug Resistancexe2x80x9d, J. Natl. Cancer Inst., 80:14-20 (1988). This xe2x80x9ccalcium channel blockerxe2x80x9d increases the cytotoxicity by increasing the intracellular accumulation of drugs, probably in part due to an effect on P-glycoprotein or other transport proteins. The toxicity of these and similar substances, such as quinidine, reduces their clinical usefulness.
In view of the foregoing, the present invention provides an effective substance for preventing or reducing resistance formation against treatment with cytostatic agents and provides for a corresponding drug. The present invention provides for a composition for preventing or reducing the formation of resistance in cytostatic treatment, the composition combining at least one 5xe2x80x2 substituted nucleoside with at least one cytostatic agent.
The present invention provides for a method of producing a composition for preventing or reducing formation of resistance in cytostatic treatment comprising combining (E)-5-(2-bromovinyl-)2xe2x80x2-deoxyuridine (BVDU), a salt thereof, or BVDU in protected or in prodrug form with at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil.
The present invention also provides for a composition for preventing or reducing the formation of resistance in cytostatic treatment comprising:
(E)-5-(2-bromovinyl-)2xe2x80x2-deoxyuridine (BVDU), a salt thereof, or BVDU in protected or in prodrug form, and
at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil, wherein the quantity of BVDU is effective to produce a concentration of 0.02 xcexcg/ml to 10 xcexcg/ml in blood.
The composition may also include at least one conventional carrier and may include at least one auxiliary material.
BVDU may be present in an amount effective to produce a concentration of 0.05 xcexcg/ml to 5 xcexcg/ml in blood.
Preferably, the at least one cytostatic agent may be selected from one or more of 20 alkaloids, alkylating agents, anti-metabolites, antibiotics, or cisplatin.
The present invention also provides for a method of reducing resistance in cytostatic treatment comprising delivering therapeutically-effective amount of at least one cytostatic agent, which is an anti-carcinogenic agent and which is not 5-fluorouracil, and therapeutically-effective amount of BVDU a salt thereof, or BVDU in protected or in prodrug form.
BVDU may be present in a therapeutically-effective amount, i.e., an amount effective to produce a blood concentration of BVDU from about 0.02 xcexcg/ml to about 10 xcexcg/ml. Preferably, BVDU is present in an amount effective to produce a blood concentration of from about 0.05 xcexcg/ml to about 5 xcexcg/ml.
The at least one cytostatic agent may be selected from one or more of alkaloids, alkylating agents, antibiotics, antimetabolites, hormonal agonists/antagonists or steroids and combinations.
The alkylating agents may be selected from one or more of bisulfan, carboplatin, cisplatin, melphalan, cyclophosphamide, ifosfamide, chloroambucil, mechlorethamine HCl, carmustine, lomustine, polifeprosan 20 or streptozocin sterile powder.
The antibiotics may be selected from one or more of doxorubicin hydrochloride, bleomycin sulfate, daunorubicin HCl, diactinomycin, daunorubicin citrate, doxorubicin HCl, idarubicin HCl, plicamycin, mitomycin, pentostatin, mitoxantrone, doxorubicin hydrochloride, or valrubicin.
The antimetabolites may be selected from one or more of cytarabine, fludarabine phosphate, floxuridine, cladribine, methotrexate, mercaptopurine, thioguanine, or capecitabine.
The hormonal agonists/antagonists may be selected from androgens, antiandrogens, antiestrogens, estrogen and nitrogen combinations, estrogens, gonadotropin releasing hormone (GNRH) analogues, progestins or immunomudulators.
The androgens may be selected from one or more of methyltestosterone, nilutamide, or testolactone.
The antiandrogens may be selected from one or more of bicalutamide or flutamide.
The antiestrogens may be selected from one or more of anastrozole, toremifene citrate, or tamoxifen citrate.
The the estrogen and nitrogen combinations is estramustine phosphate sodium.
The estrogens may be selected from one or more of ethinyl estradiol, esterified estrogen, or conjugated estrogen.
The GNRH analogues may be selected from one or more of leuprolide acetate or goserelin acetate.
The progestins may be selected from one or more of medroxyprogesterone acetate or magestrol acetate.
The immunomodulators may be selected from one or more of levamisole hydrochloride or aldesleukin.
The cytostatic agent may also be selected from one or more of allopurinol sodium, dolasetron mesylate, pamidronate disodium, etidronate disodium, fluconazole, erythropoietin, levamisole hydrochloride, amifostine, granisetron hydrochloride, leucovorin, sargramostim, dronabinol, 2-mercaptoethane sulfonate, filgrastim, octreotide acetate, pilocarpine hydrochloride, dexrazoxane, ondansetron hydrochloride, irinotecan hydrochloride, dacarbazine, asparaginase, etoposide phosphate, gemcitabine HCl, trastuzumab, altretarnine, topotecan hydrochloride, hydroxyurea, mitotane, interferon alfa-2b, procarbazine hydrochloride, vinorelbine tartrate, pegaspargase, vincaleukoblastine, 22-oxo, sulfate (1:1)(salt), denileukin diftitox, rituximab, aldesleukin, interferon alfa-2a, docetaxel, paclitaxel, BCG Live (Intravesical), BCG Live, vinblastine sulfate, etoposide, teniposide, or tretinoin.